Malformations of the heart are one of the most common congenital defects in human. They affect millions of children worldwide, and increasing number of adults are also suffering from structural heart defects. Anomalies in the cardiac outflow tract occur in many congenital heart disease and genetic syndromes such as DiGeorge and Down syndrome. Although neural crest cell dysfunction underlies the majority of those cardiac outflow malformations, relatively little is known about the mechanisms of neural crest cell development. Mice lacking Pbx1 gene have severe anomalies in the cardiac outflow tract and great arteries, consistent with neural crest cell defects. These mice provide an animal model to study the mechanisms that govern the formation of cardiac outflow region. I propose to investigate (1) the migratory behavior of neural crest cells in Pbx1-null mice, (2) the differentiation of neural crest cells in the absence of Pbx1 and (3) whether Pbx1 functions cell autonomously in cardiac neural crest cells to regulate cardiac development. These studies will provide important insights to the mechanisms of how neural crest cells contribute to heart development, and this will present new opportunities for better diagnosis and treatment of diseases. [unreadable] [unreadable] [unreadable]